Summary Progressive and fatal neurodegenerative disorders, including Alzheimer disease (AD) and Parkinson disease (PD), represent a huge unmet need for treatment. The low efficacy of current treatment methods is partially due to the presence of various obstacles in the delivery routes, with the blood? brain barrier (BBB) being the main barrier of drug delivery to the brain. In order to develop effective therapies for these disorders, efficient and safe drug delivery systems to cross the BBB are needed. Promising results have been obtained by using synthetic nanoparticles or liposomes as drug carriers, but these systems still face challenges such as immune activation mediated rapid clearance of the vehicle and concomitant decrease in efficacy when re-administered. To overcome the limitations, researchers in recent studies have developed targeted systems that use self-derived exosomes, the membrane vesicles secreted by most cell types and act as carriers of biomolecules between cells, for nucleic acid or protein delivery to the brain, and demonstrated their beneficial properties and efficiency in animal models of neurodegenerative diseases, though the targeting doesn't seem to be cell type or system specific. In this study, based on our recent findings on central nervous system (CNS) cell-type specific exosomes, we propose to further develop exosome-based but more efficient and functional specific delivering systems. Specifically, our previous studies have demonstrated that red blood cell (RBC)-derived exosomes/microvesicles could cross the BBB, particularly under inflammatory conditions, and that exosomes carrying CNS cell specific surface markers (e.g., L1CAM for neurons and CNPase for oligodendrocytes) could be transported from the brain into peripheral blood and re-enter the brain readily even without peripheral inflammation. Therefore, we hypothesize that exosomes derived from hematopoietic stem cells (HSCs)/RBC progenitors, when modified to express brain cell-specific surface markers, can cross the BBB from peripheral blood more efficiently and deliver nucleic acid or protein cargos into the target brain cells more specifically. In this study, we will first develop such exosomal delivery systems by engineering cultured human or mouse HSCs to express brain cell-specific surface markers, with or without additional previously identified strategies to enhance transportation efficiency and stability, and verify the cellular uptake and BBB crossing of the modified exosomes in in vitro and in vivo models. We also plan to engineer exosomes to carry additional surface markers to target more specific neuronal subpopulations, and finally test the delivery of potential treatments in neurodegenerative disease animal models. This proposed study will likely develop a more efficient and targeted drug delivery system for neurodegenerative diseases, and provide the foundation for future studies of effective and targeted treatments.